The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells.

Abstract

Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-γ plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83+ conventional DCs, and a decrease in immature activated Tim3+ NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines.

• Authors: Caroline Jochems, Massimo Fantini, Romaine I Fernando, Anna R Kwilas, Renee N Donahue, Lauren M Lepone, Italia Grenga, Young-Seung Kim, Martin W Brechbiel, James L Gulley, Ravi A Madan, Christopher R Heery, James W Hodge, Robert Newton, Jeffrey Schlom, Kwong Y Tsang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 25 Pg. 37762-37772 (Jun 21 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27192116 (Publication Type: Journal Article)

Chemical References

• Cancer Vaccines
• IDO1 protein, human
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Lipopolysaccharides
• Oximes
• Peptides
• Sulfonamides
• Kynurenine
• epacadostat
• Interferon-gamma
• Granulocyte-Macrophage Colony-Stimulating Factor
• Tryptophan

Topics

• Adult
• Aged
• Cancer Vaccines (pharmacology)
• Dendritic Cells (drug effects, immunology)
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Healthy Volunteers
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors)
• Interferon-gamma (metabolism)
• Kynurenine (chemistry)
• Leukocytes, Mononuclear (metabolism)
• Lipopolysaccharides (chemistry)
• Lymphocyte Activation (immunology)
• Male
• Middle Aged
• Oximes (pharmacology)
• Peptides (chemistry)
• Phenotype
• Sulfonamides (pharmacology)
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• Tryptophan (chemistry)
• Young Adult